Biaromatic amido compounds and pharmaceutical/cosmetic compositions comprised thereof

ABSTRACT

Novel pharmaceutically/cosmetically-active biaromatic amido compounds have the structural formula (I): ##STR1## in which Ar is a radical selected from among those of the following formulae (a)-(e): ##STR2## and are useful for the treatment of a wide variety of disease states, whether human or veterinary, for example dermatological, rheumatic, respiratory, cardiovascular and ophthalmological disorders, as well as for the treatment of mammalian skin and hair conditions/disorders.

BACKGROUND OF THE INVENTION TECHNICAL FIELD OF THE INVENTION

The present invention relates to novel amide-derived biaromaticcompounds and to pharmaceutical/cosmetic compositions comprised thereof;the subject amido compounds are especially useful in human or veterinarymedicine, or alternatively in cosmetic compositions.

SUMMARY OF THE INVENTION

The compounds according to the invention display marked activity in thefields of cell differentiation and proliferation, and are particularlyuseful in the topical and systemic treatment of dermatologicalconditions associated with a keratinization disorder, dermatologicalconditions (and the like) including an inflammatory and/orimmunoallergic component, and dermal or epidermal proliferations,whether benign or malignant. The subject compounds can, in addition, beused for the treatment of degeneration diseases of the connectivetissue, for combating skin aging, whether photoinduced or chronologic,and for treating cicatrization disorders. They are also useful forophthalmological applications, especially for the treatment ofcorneopathies.

The compounds according to this invention are also useful for thetreatment of osteoporosis, and for the treatment of viral diseases, aswell as for the treatment of any condition associated withhypervitaminose A. In general, they are useful for the treatment of anydisease state which is associated with a modification of the expressionof receptors belonging to the superfamily of steroid and thyroid hormonereceptors.

Too, the compounds according to the invention can be formulated intocosmetic compositions for body and hair care.

Briefly, the biaromatic amido compounds according to the invention havethe following structural formula (I): ##STR3## in which Ar is a radicalselected from among those of the following formulae (a)-(e): ##STR4## inwhich R₅ and R₆ are as defined below; Z is --CO--NR₇ --; R₁ is (i) a--CH₃ radical, (ii) a radical --CH₂ --O--R₆, (iii) a radical --O--R₆,(iv) a radical --CO--R₈ or (v) a radical --S(O)_(t) R₉, wherein R₆, R₈,R₉ and t are as defined below; X and Y may be taken separately, in whichevent X is a hydrogen atom or a lower alkyl radical, and Y is a radicalof the formula --(CH₂)_(n) --CH₃ or of the formula --(CH₂)_(n) --R₁₀, orX and Y may be taken together, in which event X and Y together form,with the carbon atom from which they depend, a single radical containinga double bond, selected from among those of the formulae═N--O--(CH₂)_(n) --R₁₀, ═CH--(CH₂)_(m) --R₁₀, ═N--O--(CH₂)₂ --O--CH₂--CH₃, ═N--O--CH₂ --O--CH₂ --CH₂ --O--CH₃, and ═CH--(CH₂)_(m) --CH₃,wherein R₁₀, m and n are as defined below; R₂ and R₃, taken separately,are each a hydrogen atom, a linear or branched alkyl radical having from1 to 20 carbon atoms, a radical --OR₆ or a radical --SR₆, wherein R₆ isas defined below, with the proviso that R₂ and R₃ cannot simultaneouslybe a hydrogen atom, a radical --OR₆ or a radical --SR₆, or R₂ and R₃together form, with the adjacent aromatic ring from which they depend, a5- or 6-membered ring optionally substituted by methyl radicals and/oroptionally interrupted by an oxygen or sulfur atom or by an --SO-- or--SO₂ -- radical; R₄ is a hydrogen atom, a halogen atom, a lower alkylradical or a radical --OR₆, wherein R₆ is as defined below, with theproviso that R₅ has the same definition as R₄ ; R₆ is a hydrogen atom, alinear or branched alkyl radical having from 1 to 20 carbon atoms or aradical --CO--R₁₁, wherein R₁₁ is as defined below; R₇ is a hydrogenatom or a lower alkyl radical; R₈ is (a) a hydrogen atom, (b) a loweralkyl radical, (c) a radical of the formula: ##STR5## wherein R' and R"are as defined below, or (d) a radical --OR₁₂, wherein R₁₂ is as definedbelow; R₉ and R₁₁, which may be identical or different, are each a loweralkyl radical; R₁₀ is (i) a radical --OR₆, (ii) a radical --CO--R₈,(iii) a radical of the formula: ##STR6## wherein R' and R" are asdefined below, (iv) an optionally substituted aryl radical, (v) aheterocyclic radical, or (vi) a C₃ or C₆ cycloaliphatic radical; R₁₂ isa hydrogen atom, a linear or branched alkyl radical having from 1 to 20carbon atoms, an alkenyl radical, a mono- or polyhydroxyalkyl radical,an optionally substituted aryl or aralkyl radical, or a sugar residue oran amino acid or peptide residue; R' and R", which may be identical ordifferent, are each a hydrogen atom, a lower alkyl radical, a mono orpolyhydroxyalkyl radical, an optionally substituted aryl radical or anamino acid or peptide or sugar residue with the proviso that R' and R"may together form, with the nitrogen atom from which they depend, aheterocycle; m is an integer ranging from 1 to 20; n is an integerranging from 2 to 20; and t is an integer equal to 0, 1 or 2.

This invention also features the salts of the compounds of formula (I)in the event that R₁ is a carboxylic acid functional group, as well asthe optical and geometric isomers thereof. When the compounds accordingto the invention are in the form of salts, they are preferably salts ofan alkali or alkaline earth metal, or alternatively, of zinc or of anorganic amine.

BRIEF DESCRIPTION OF THE DRAWINGS

SCHEMATICS IN FIGS. 1 AND 2 set forth reaction schemes/mechanismsillustrating syntheses for the preparation of the biaromatic amidocompounds according to the present invention.

DETAILED DESCRIPTION OF BEST MODE AND PREFERRED EMBODIMENTS OF THEINVENTION

More particularly according to the present invention, by "lower alkylradical" is intended an alkyl radical having from 1 to 6 carbon atoms,preferably methyl, ethyl, isopropyl, butyl, tert-butyl and hexylradicals.

By "linear or branched alkyl radical having from 1 to 20 carbon atoms"is preferably intended methyl, ethyl, propyl, 2-ethylhexyl, octyl,dodecyl, hexadecyl and octadecyl radicals.

By "monohydroxyalkyl radical" is intended a radical preferably having 2or 3 carbon atoms, especially a 2-hydroxyethyl, 2-hydroxypropyl or3-hydroxypropyl radical.

By "polyhydroxyalkyl radical" is intended a radical preferably having 3to 6 carbon atoms and 2 to 5 hydroxyl groups, such as2,3-dihydroxypropyl, 2,3,4-trihydroxybutyl or 2,3,4,5-tetrahydroxypentylradicals, or a pentaerythritol residue.

By "aryl radical" is preferably intended a phenyl radical optionallysubstituted by at least one halogen atom, or at least one hydroxyl ornitro functional group.

By "aralkyl radical" is preferably intended a benzyl or phenethylradical optionally substituted by at least one halogen atom, or at leastone hydroxyl or nitro functional group.

By "alkenyl radical" is intended a radical preferably having from 1 to 5carbon atoms and one or more sites of ethylenic unsaturation, such as,more particularly, the allyl radical.

By "sugar residue" is intended a residue derived especially fromglucose, galactose or mannose, or alternatively from glucuronic acid.

By "amino acid residue" is especially intended a residue derived fromlysine, glycine or aspartic acid, and by "peptide residue" is moreparticularly intended a dipeptide or tripeptide residue prepared via thecombination of amino acids.

By "C₃ or C₆ cycloaliphatic radical" is more particularly intended acyclopropyl or cyclohexyl radical.

Lastly, by "heterocycle" is preferably intended a piperidino,morpholino, pyrrolidino or piperazino radical, optionally substituted atthe 4-position by a C₁ -C₆ alkyl radical or a mono- or polyhydroxyalkylradical as defined above.

When R₄ and R₅ represent a halogen atom, it is preferably a fluorine,chlorine or bromine atom.

Among the compounds of formula (I) according to the present invention,particularly representative are the following:

anti-4-α-Hydroxyhexylimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoicacid;

syn-4-α-Hydroxyhexylimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoicacid;

syn-4-α-Methoxycarbonylpentylimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoicacid;

syn-4-α-Hydroxyoctyloxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoicacid;

trans-4-α-Hydroxyoctyloxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!-benzoicacid;

syn-4-α-Hydroxyheptyloxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!-benzoicacid;

trans-4-α-Hydroxyheptyloxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!-benzoicacid;

syn-4-α-Hydroxypropyloxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!-benzoicacid;

trans-4-α-Hydroxypropyloxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!-benzoicacid;

syn-4-α-Ethoxycarbonylpropyloxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2naphthyl)acetamido!-benzoicacid;

syn-4-α-Hydroxydecyloxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!-benzoicacid;

syn-4-α-Hydroxynonyloxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!-benzoicacid;

syn-4-α-Benzyloxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!-benzoicacid;

syn-4-α-Methoxyethoxymethoxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!-benzoicacid;

Allyl syn-4-α-ethoxycarbonylpropyloxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-acetamido!benzoate;

(E)-4-2-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-nonenamido!benzoicacid;

(Z)-4-2-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-nonenamido!benzoicacid;

(E)-4-2-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-undecenamido!benzoicacid;

(E)-4-2-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-undecenamido!phenylcarboxamide;

(E)-4-2-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-undecenamido!benzenemethanol;

(E)-4-2-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-undecenamido!phenol;

(Z)-4-2-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-undecenamido!benzoicacid;

(E)-4-2-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-hexadecenamido!benzoicacid;

(Z)-4-2-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-hexadecenamido!benzoicacid.

According to the present invention, the compounds of formula (I) whichare more particularly preferred are those in which R₁ represents theradical --COR₈, and X and Y together form, with the carbon atom fromwhich depend, a radical selected from among those of the followingformulae:

    ═N--O--(CH.sub.2).sub.n --R.sub.10

    ═CH--(CH.sub.2).sub.m --R.sub.10

    ═N--O--(CH.sub.2).sub.2 --O--CH.sub.2 --CH.sub.3

    ═N--O--CH.sub.2 --O--CH.sub.2 --CH.sub.2 --O--CH.sub.3

    ═CH--(CH.sub.2).sub.m --CH.sub.3,

wherein R₈, R₁₀, m and n are as defined above.

The present invention also features the processes for preparing thecompounds of formula (I) via the reaction schemes described below andillustrated in the FIGS. 1 and 2 of the Drawings.

The derivatives of formula (1a) can be prepared by a series of reactionsshown in FIG. 1, first comprising a Friedel-Crafts type reaction betweenthe aromatic compound of formula (1) and the ethoxallyl chloride in thepresence of a Lewis acid such as AlCl₃, followed by saponification ofthe ester functional group in the presence of a base, such as sodium orlithium hydroxide, in an alcoholic solvent or THF. The derivative offormula (3) thus obtained is coupled with the aniline of formula (4)either via the acid chloride or in the presence of dicyclohexylamine anddimethylaminopyridine in a solvent such as THF or dichloromethane. Byreacting the compound of formula (5) with hydroxylamine in an alcoholicsolvent such as ethyl alcohol, the compound of formula (6) is obtainedwhich is then alkylated by a halogenated compound of formula (7),preferably iodine- or bromine-containing, either via itssodium-containing derivative in DMF, or in the presence of potassiumcarbonate in a solvent such as methyl ethyl ketone. The derivatives offormula (1) can be prepared by a series of reactions, shown in FIG. 2,entailing a Horner-Emmons type reaction between the glyoxylic compoundof formula (3) and a phosphonate of formula (8). The derivative offormula (9) thus obtained is then coupled with the aniline of formula(4) either via the acid chloride or in the presence of dicyclohexylamineand of dimethylaminopyridine in a solvent such as THF ordichloromethane.

The derivatives of formula I(c) can be obtained from the compound offormula I(b) by hydrogenation utilizing a catalyst such as palladium oncarbon in a solvent such as dioxane or ethyl alcohol.

When R₁ represents the --COOH radical, the compounds are preferablyprepared by protecting R₁ with an allyl, benzyl or tert-butyl typeprotecting group. The conversion into the free form can be carried out:

(1) in the event of an allyl type protecting group, by means of acatalyst such as certain transition metal complexes, for exampletetrakis(triphenylphosphine)palladium(0), in the presence of a secondaryamine such as morpholine or the sodium salt of diethyl malonate;

(2) in the event of a benzyl type protecting group, by debenzylation inthe presence of hydrogen, by means of a catalyst such as palladium oncarbon, in an alcoholic solvent such as ethyl alcohol or in dioxane;

(3) in the event of a tert-butyl type protecting group, by means oftrimethylsilane iodide or of trifluoroacetic acid, in a solvent such asdichloromethane.

The present invention also features therapeutic/pharmaceuticalapplications of the compounds of formula (I).

Depending on the nature of the particular radicals selected, thesecompounds exhibit either an agonist activity in the test fordifferentiation of mouse embryonic teratocarcinoma cells (F9) (CancerResearch, 43, p. 5268 (1983) and/or in the test for inhibition ofornithine decarboxylase after induction with TPA in mice (CancerResearch, 38, p. 793-801 (1978) or, on the other hand, an antagonistactivity with respect to the expression of one or more biologicalmarkers in the test for differentiation of mouse embryonicteratocarcinoma cells (F9) (Skin Pharmacol., 3, pp. 156-267 (1990)and/or on the in vitro differentiation of human keratinocytes (Anal.Biochem., 192, pp. 232-236 (1991)).

The compounds according to the invention are particularly suitable inthe following fields of therapy:

(1) for treating dermatological conditions associated with akeratinization disorder related to differentiation and to proliferation,especially for treating acne vulgaris or comedo-type, polymorphic orrosacea acnes, nodulocystic acne or acne conglobata, senile acnes,secondary acnes such as solar acne, acne medicamentosa or occupationalacne;

(2) for treating other types of keratinization disorders, especiallyichthyoses, ichthyosiform states, Darier's disease, keratoses palmarisand plantaris, leucoplakias and leucoplakia-like states, skin or mucous(buccal) lichen;

(3) for treating other dermatological conditions associated with akeratinization disorder manifesting an inflammatory and/orimmunoallergic component, and, especially, all forms of psoriasis,whether cutaneous, mucous or ungual, and even arthropathic psoriasis,or, alternatively, skin atopy, such as eczema or respiratory atopy oralternatively gingival hypertrophy; the compounds can also be used fortreating inflammatory conditions not exhibiting keratinization disorder;

(4) for treating all dermal or epidermal proliferations, whether benignor malignant, whether or not they are of viral origin, such as verrucavulgaris, verruca plana and epidermodysplasia verruciformis, oral orflorid papillomatoses and proliferations which can be induced byultraviolet radiation, especially in the case of baso- and spinocellularepitheliomas;

(5) for treating other dermatological disorders such as bullousdermatoses and collagen diseases;

(6) for treating certain ophthalmological disorders, especiallycorneopathies;

(7) for repairing or combating skin aging, whether photoinduced orchronologic, or to reduce pigmentations and actinic keratoses, or allpathologies associated with chronologic or actinic aging;

(8) for preventing or curing the stigmas of epidermal and/or dermalatrophy induced by local or systolic corticosteroids, or any other formof skin atrophy;

(9) for preventing or treating cicatrization disorders or for preventingor for repairing vibices;

(10) for combating disorders of the sebaceous function, such as acnehyperseborrhoea or simple seborrhoea;

(11) for the treatment or prevention of cancerous or precancerousstates;

(12) for the treatment of inflammatory conditions such as arthritis;

(13) for the treatment of any condition of viral origin at the level ofthe skin or in general;

(14) for the prevention or treatment of alopecia;

(15) for the treatment of dermatological or general conditions includingan immunological component;

(16) for the treatment of conditions of the cardiovascular system, suchas arteriosclerosis;

(17) for the treatment or prevention of osteoporosis;

(18) for the treatment of seasonally-related depression.

For the aforesaid therapeutic or pharmaceutical applications, thecompounds according to the invention can advantageously be used incombination with other compounds displaying retinoid-type activity, withthe D vitamins or derivatives thereof, with corticosteroids, withanti-free radical agents, with α-hydroxy or α-keto acids or derivativesthereof, or alternatively with ion channel blockers. By "D vitamins orderivatives thereof" are intended, for example, the derivatives ofvitamin D₂ or D₃ and in particular 1,25-dihydroxyvitamin D₃. By"anti-free radical agents" are intended, for example, α-tocopherol,superoxide dismutase, ubiquinol or certain metal-chelating agents. By"α-hydroxy or α-keto acids or derivatives thereof" are intended, forexample, lactic, malic, citric, glycolic, mandelic, tartaric, glycericor ascorbic acids or salts, amides or esters thereof. By "ion channelblockers" are intended, for example, minoxidil(2,4-diamino-6-piperidinopyrimidine 3-oxide) and derivatives thereof.

The present invention thus also features medicinal compositionscontaining at least one compound of formula (I), one of its optical orgeometric isomers, or one of its pharmaceutically acceptable salts orother derivatives thereof.

The pharmaceutical/therapeutic compositions of this invention, intendedespecially for the treatment of the aforesaid disease states comprise acarrier, diluent or vehicle which is pharmaceutically acceptable andcompatible with the mode or regime of administration selected for thegiven composition, at least one compound of formula (I), one of itsoptical or geometric isomers or one of the salts, etc., thereof.

The administration of the compounds according to the invention can becarried out systemically, enterally, parenterally, topically orocularly.

For enteral administration, the medicinal/pharmaceutical compositionsmay be in the form of tablets, gelatin capsules, sugar-coated tablets,syrups, suspensions, solutions, elixirs, powders, granules, emulsions,microspheres or nanospheres or lipid or polymeric vesicles which permita controlled release. For parenteral administration, the compositionsmay be in the form of solutions or suspensions for perfusion or forinjection.

The compounds according to the invention are generally administered at adaily dose of about 0.01 mg/kg to 100 mg/kg of body weight, and this atthe regime or rate of 1 to 3 doses per diem.

For topical administration, the pharmaceutical compositions based oncompounds according to the invention are more particularly intended forthe treatment of the skin and the mucous membranes and can be providedin the form of ointments, creams, milks, pommades, powders, impregnatedpads, solutions, gels, sprays, lotions or suspensions. They may also beprovided in the form of microspheres or nanospheres or lipid orpolymeric vesicles or polymeric patches and hydrogels which permit acontrolled release.

These compositions for topical administration may, moreover, be providedeither in anhydrous form or in an aqueous form according to theparticular clinical indication.

For ocular administration, they are principally collyria.

These compositions for topical or ocular application contain at leastone compound of formula (I), or one of its optical or geometric isomersor, alternatively, one of its salts, etc., at a concentration preferablyranging from 0.001% to 5% by weight relative to the total weight of thecomposition.

The compounds of formula (I) according to the invention also findapplication in the cosmetic field, in particular for body and hair careand especially for the treatment of skins with acne tendency, for hairregrowth, against loss, for combating the greasy appearance of the skinor the hair, in the protection against the harmful effects of the sun orin the treatment of physiologically dry skins, for preventing and/or forcombating photoinduced or chronologic aging.

For cosmetic applications, the compositions of the invention may,moreover, be advantageously used in combination with other compoundsdisplaying retinoid-type activity, with the D vitamins or derivativesthereof, with corticosteroids, with anti-free radical agents, withα-hydroxy or α-keto acids or derivatives thereof, or alternatively withion channel blockers, all of these different active agents being asdefined above.

The present invention therefore also features cosmetic compositionscomprising a carrier, diluent or vehicle which is cosmeticallyacceptable and suitable for a topical application, at least one compoundof formula (I) or one of its optical or geometric isomers or one of itssalts. Such cosmetic compositions are advantageously presented in theform of a cream, a milk, a lotion, a gel, microspheres or nanospheres orlipid or polymeric vesicles, a soap or a shampoo.

The concentration of the compound of formula (I) in the cosmeticcompositions according to the invention advantageously ranges from0.001% to 3% by weight relative to the total composition.

The medicinal and cosmetic compositions according to the invention may,in addition, contain inert or even pharmacodynamically or cosmeticallyactive additives and adjuvants, or combinations of these additives, and,especially: wetting agents; depigmenting agents such as hydroquinone,azelaic acid, caffeic acid or kojic acid; emollients; moisturizingagents such as glycerol, PEG 400, thiamorpholinone and its derivativesor alternatively urea; antiseborrhoeic or antiacne agents such asS-carboxymethylcysteine, S-benzylcysteamine, salts or derivativesthereof, benzoyl peroxide; antibiotics such as erythromycin and estersthereof, neomycin, clindamycin and esters thereof, tetracyclines;antifungal agents such as ketoconazole or4,5-polymethylene-3-isothiazolidones; agents promoting hair regrowth,such as Minoxidil (2,4-diamino-6-piperidinopyrimidine 3-oxide) andderivatives thereof, Diazoxide(7-chloro-3-methyl-1,2,4-benzothiadiazine-1,1-dioxide) and Phenytoin(5,4-diphenyl-2,4-imidazolidinedione); non-steroidal anti-inflammatoryagents; carotenoids and especially β-carotene; anti-psoriatic agentssuch as anthralin and derivatives thereof; and, lastly,5,8,11,14-eicosatetraynoic and 5,8,11-eicosatrynoic acids and esters andamides thereof.

The compositions according to the invention may also contain taste- orflavor-enhancing agents, preservatives such as parahydroxybenzoic acidesters, stabilizing agents, moisture regulating agents, pH regulatingagents, osmotic pressure modifying agents, emulsifying agents, UV-A andUV-B screening agents, antioxidants such as α-tocopherol, butylatedhydroxyanisol or butylated hydroxytoluene.

In order to further illustrate the present invention and the advantagesthereof, the following specific examples are given, it being understoodthat same are intended only as illustrative and in nowise limitative.

EXAMPLE 1 Preparation of allyl syn-4-α-hydroxyhexyloxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoate

(a) Preparation of ethyl5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylglyoxylate:

14.5 g (0.109 mol) of aluminum chloride and 100 ml of dichloromethanewere introduced into a three-necked flask and a mixture of 11.7 g (62mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalene and of 8ml (71 mmol) of ethoxalyl chloride in 100 ml of dichloromethane wasadded dropwise and the mixture was stirred at room temperature for onehour. The reaction medium was poured into ice, extracted with ethylether, the organic phase decanted off, dried over magnesium sulfate andevaporated. The residue obtained was purified by chromatography on asilica column, eluted with a mixture of dichloromethane and hexane(30/70). After evaporation of the solvents, 16.5 g (93%) of the expectedester were recovered in the form of a slightly yellow oil.

(b) Preparation of5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylglyoxylic acid:

16 g (55.6 mmol) of ethyl5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylglyoxylate and 50 ml ofethyl alcohol were introduced into a round-bottomed flask. A solution of2.5 g (58.5 mmol) of sodium hydroxide in 50 ml of water was added andthe mixture was heated at reflux for one hour. The reaction medium wasevaporated to dryness, taken up in water and ethyl ether, the aqueousphase decanted off, acidified to pH 1 with concentrated hydrochloricacid, extracted with ethyl ether, the organic phase decanted off, driedover magnesium sulfate and evaporated. 14 g (97%) of5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylglyoxylic acid wererecovered in the form of a colorless oil.

(c) Preparation of5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylglyoxyloyl chloride:

2.6 g (10 mmol) of5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylglyoxylic acid in 50 mlof dichloromethane were introduced into a round-bottomed flask, 2 ml (10mmol) of dicyclohexylamine were added and the mixture was stirred atroom temperature for one hour. 800 μl (10 mmol) of thionyl chloride werethen added dropwise and the mixture was stirred at room temperature forone hour. The mixture was evaporated to dryness, taken up in ethylether, the dicyclohexylamine salt filtered and the filtrate evaporated.2.8 g (100%) of crude acid chloride were obtained, which acid chloridewas employed as is in the synthesis to follow.

(d) Preparation of allyl4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthoylcarboxamido)benzoate:

3.6 g (20 mmol) of allyl 4-aminobenzoate, 2.8 ml (20 mmol) oftriethylamine and 50 ml of THF were introduced into a round-bottomedflask. A solution of 5.6 g (20 mmol) of5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylglyoxyloyl chloride in50 ml of THF was added dropwise and the mixture was stirred at roomtemperature for four hours. The reaction medium was poured into water,extracted with ethyl ether, the organic phase decanted off, dried overmagnesium sulfate and evaporated. The residue obtained was purified bychromatography on a silica column, eluted with a mixture ofdichloromethane and hexane (40/60). After evaporation of the solvents, 2g (46%) of the expected allyl ester were recovered in the form of aslightly yellow oil.

(e) Preparation of allyl 4-α-hydroxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoate:

1.7 g (4 mmol) of allyl4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthoylcarboxamido)benzoate,1.1 g (16 mmol) of hydroxylamine hydrochloride and 50 ml of ethanol wereintroduced into a round-bottomed flask. 16 ml of NaOH (1N) were addeddropwise and the mixture was heated at reflux for 4 hours. The reactionmedium was evaporated to dryness, the residue taken up in water,extracted with ethyl ether, the organic phase decanted off, dried overmagnesium sulfate and evaporated. The residue obtained waschromatographed on a silica column, eluted with a mixture ofdichloromethane and ethyl ether (98/2). After evaporation of thesolvents, 1.6 g (94%) of the expected compound of melting point 176°-7°C. was obtained.

(f) Synthesis of allyl syn-4-α-hydroxyhexyloxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoate:

3.25 g (7.5 mmol) of allyl 4-α-hydroxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoate,1 g (7.5 mmol) of potassium carbonate and 100 ml of methyl ethyl ketonewere introduced into a round-bottomed flask. 1 ml (7.5 mmol) of6-bromohexanol was added and the mixture was heated at reflux for 24hours. The reaction medium was filtered, the filtrate evaporated todryness, taken up in water and ethyl ether, the organic phase wasdecanted off, dried over magnesium sulfate and evaporated. The residueobtained was purified by chromatography on a silica column, eluted withdichloromethane. 3.3 g (82%) of the expected compound were thusrecovered in the form of a yellow oil.

EXAMPLE 2 Preparation of syn-4-α-hydroxyhexyloxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-napthyl)acetamido!benzoicacid

3.3 g (6.2 mmol) of allyl syn-4-α-hydroxyhexyloxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-napthyl)acetamido!benzoate,230 mg (0.2 mmol) of tetrakis(triphenylphosphine)palladium(0) and 100 mlof THF were introduced into a three-necked flask, under a nitrogenstream. 2.7 ml (31 mmol) of morpholine were then added dropwise and themixture was stirred at room temperature for 2 hours. The reaction mediumwas evaporated to dryness, taken up in water, acidified to pH 1,extracted with ethyl ether, the organic phase was decanted off, washedwith water, dried over magnesium sulfate and evaporated. The residueobtained was purified by chromatography on a silica column, eluted withethyl ether and 2 g (65.5%) of syn-4-α-hydroxyhexyloxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoicacid of melting point 183°-6° C. were recovered.

EXAMPLE 3 Preparation of anti-4-α-hydroxyhexyloxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoicacid

800 mg (1.7 mmol) of syn-4-α-hydroxyhexyloxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoicacid and 600 ml of methanol were introduced into a photochemical reactorand stirred for 48 hours at room temperature while irradiating (mediumpressure Hanovia lamp, with no filter). The reaction medium wasevaporated and the residue obtained was purified by chromatography on asilica column, eluted with a mixture of dichloromethane and methanol(98/2). After evaporation of the solvents, 470 mg (59%) of anti-4-α-hydroxyhexyloxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoicacid of melting point 178°-81° C. were recovered.

EXAMPLE 4 Preparation of allyl syn-4-α-ethoxycarbonylpentyloxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoate

Following the basic procedure of Example 1 (f), 3.25 g (7.5 mmol) ofallyl 4-α-hydroxyimino(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2naphthyl)acetamido!benzoatewere reacted with 1.3 ml (7.5 mmol) of ethyl 6-bromohexanoate. 1.7 g(39.5%) of allyl syn-4-α-ethoxycarbonylpentyloxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoatewere obtained in the form of a slightly yellow oil.

EXAMPLE 5 Preparation of syn-4-α-ethoxycarbonylpentyloxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoicacid

Following the basic procedure of Example 2, beginning with 1.7 g (3mmol) of allyl syn-4-α-methoxycarbonyl-pentyloxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoate,1.1 g (70%) of syn-4-α-ethoxycarbonylpentyloxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoicacid of melting point 152.4° C. was obtained.

EXAMPLE 6 Preparation of syn-4-α-hydroxyoctyloxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoicacid

(a) Preparation of allyl syn-4-α-hydroxyoctyloxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoate:

Following the basic procedure of Example 1 (f), 2.2 g (5 mmol) of allyl4-α-hydroxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoatewere reacted with 870 μl (5 mmol) of 8-bromo-1-octanol. 2 g (70%) of theexpected allyl ester were recovered in the form of a colorless oil afterpurification by chromatography on a silica column eluted withdichloromethane.

(b) Synthesis of syn-4-α-hydroxyoctyloxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoicacid:

Following the basic procedure of Example 2, beginning with 2 g (3.5mmol) of allyl syn-4-α-hydroxyoctyloxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoate,1.3 g (70%) of the expected acid of melting point 102°-4° C. wasobtained.

EXAMPLE 7 Preparation of trans-4-α-hydroxyoctyloxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoicacid

Following the basic procedure of Example 3, beginning with 900 mg (1.7mmol) of syn-4-α-hydroxyoctyl-oxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoicacid, 390 mg (43%) of the expected trans acid of melting point 98°-100°C. were obtained.

EXAMPLE 8 Preparation of syn-4-α-hydroxyheptyloxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoicacid

(a) Preparation of allyl syn-4-α-hydroxyhenpyloxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoate:

Following the basic procedure of Example 1 (f), 2.2 g (5 mmol) of allyl4-α-hydroxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoatewere reacted with 780 μl (5 mmol) of 7-bromo-1-heptanol. 1.7 g (61%) ofthe expected allyl ester were recovered in the form of a colorless oilafter purification by chromatography on a silica column, eluted withdichloromethane.

(b) Synthesis of syn-4-αhydroxyheptyloxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoicacid:

Following the basic procedure of Example 2, beginning with 1.7 g (3.1mmol) of allyl syn-4-hydroxyheptyloxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoate,1.3 g (82%) of the expected acid of melting point 145°-55° C. wasobtained.

EXAMPLE 9 Preparation of trans-4-α-hydroxyheptyloxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoicacid

Following the basic procedure of Example 3, beginning with 900 mg (1.77mmol) of syn-4-α-hydroxyheptyl-oxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoicacid, 350 mg (39%) of the expected trans acid of melting point 118°-23°C. were obtained.

EXAMPLE 10 Preparation of syn-4-α-carboxypentyloxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoicacid

1.3 g (2.4 mmol) of syn-4-α-ethoxycarbonyl-pentyloxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoicacid and 30 ml of THF were introduced into a round-bottomed flask and 6ml of a 2N methanolic sodium hydroxide solution were added. The mixturewas stirred at room temperature for three hours, evaporated to dryness,the residue taken up in water, acidified to pH 1 with hydrochloric acidand extracted with ethyl ether. The organic phase was decanted off,dried over magnesium sulfate and evaporated. The residue obtained waspurified by chromatography on a silica column, eluted with a mixture ofdichloromethane and ethyl ether (95/5). After evaporation of thesolvents, 1.1 g (89%) of the expected acid of melting point 162°-3° C.was recovered.

EXAMPLE 11 Preparation of trans-4-α-hydroxypropyloxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-napththyl)acetamido!benzoicacid

(a) Preparation of allyl 4-α-hydroxypyropyloxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoate:

Following the basic procedure of Example 1 (f), 3.4 g (7.8 mmol) ofallyl 4-α-hydroxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoatewere reacted with 710 μl (7.8 mmol) of 3-bromo-1-propanol. 1.4 g (36%)of the syn allyl ester and 710 mg (18%) of the trans allyl ester wererecovered after purification by chromatography on a silica column,eluted with dichloromethane.

(b) Synthesis of trans-4-α-hydroxypropyloxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoicacid:

Following the basic procedure of Example 2, beginning with 710 mg (1.4mmol) of allyl trans-4-α-hydroxy-propyloxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoate,220 mg (35%) of the expected acid of melting point 209°-11° C. wereobtained.

EXAMPLE 12 Preparation of syn-4-α-hydroxypropyloxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoicacid

Following the basic procedure of Example 2, beginning with 1.4 g (2.8mmol) of syn-4-α-hydroxypropyl-oxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoate,750 mg (58%) of the expected acid of melting point 198°-204° C. wereobtained.

EXAMPLE 13 Preparation of syn-4-α-ethoxycarbonylpropyloxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoicacid

(a) Preparation of allyl syn-4-α-ethoxycarbonylpropyloxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoate:

Following the basic procedure of Example 1 (f), 4 g (9.2 mmol) of allyl4-α-hydroxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoatewere reacted with 1.8 g (9.2 mmol) of ethyl 4-bromobutanoate. 1.3 g (26%) of the expected allyl ester was recovered in the form of a colorlessoil after purification by chromatography on a silica column, eluted witha mixture of dichloromethane and heptane (50/50).

(b) Synthesis of syn-4-α-ethoxycarbonylpropyloxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-acetamido!benzoicacid:

Following the basic procedure of Example 2, beginning with 1.4 g (2.5mmol) of allyl syn-4-α-ethoxycarbonylpropyloxyimino-(5,6,7,8)-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoate,180 mg (14%) of the expected acid of melting point 120°-1° C. wereobtained.

EXAMPLE 14 Preparation of syn-4-α-hydroxydecyloxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoicacid

(a) Preparation of syn-4-α-hydroxydecyloxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoicacid:

Following the basic procedure of Example 1 (f), 2.2 g (5 mmol) of allyl4-α-hydroxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoatewere reacted with 995 μl (5 mmol) of 10-bromo-1-decanol. 1 g (35%) ofthe expected allyl ester was recovered in the form of a colorless oilafter purification by chromatography on a silica column, eluted withdichloromethane.

(b) Synthesis of syn-4-α-hydroxydecyloxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoicacid:

Following the basic procedure of Example 2, beginning with 1 g (1.7mmol) of allyl syn-4-α-hydroxydecyloxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoate,400 mg (50%) of the expected acid of melting point 145°-6° C. wereobtained.

EXAMPLE 15 Preparation of syn-4-α-hydroxynonyloxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoicacid

(a) Preparation of allyl syn-4-α-hydroxynonyloxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-acetamido!benzoate:

Following the basic procedure of Example 1 (f), 2.2 g (5 mmol) of allyl4-α-hydroxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoatewere reacted with 780 μl (5 mmol) of 7-bromo-1-heptanol. 1.7 g (61%) ofthe expected allyl ester was recovered in the form of a colorless oilafter purification by chromatography on a silica column, eluted withdichloromethane.

(b) Synthesis of syn-4-α-hydroxynonyloxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoicacid:

Following the basic procedure of Example 2, beginning with 1.3 g (2.2mmol) of allyl syn-4-α-hydroxynonyloxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoate,600 mg (50%) of the expected acid of melting point 155°-6° C. wereobtained.

EXAMPLE 16 Preparation of syn-4-α-benzyloxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoicacid

(a) Preparation of allyl syn-4-α-benzyloxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoate:

Following the basic procedure of Example 1 (f), 2.2 g (5 mmol) of allyl4-α-hydroxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoatewere reacted with 600 μl (5 mmol) of benzyl bromide. 2.6 g (98%) of theexpected allyl ester were recovered in the form of a colorless oil afterpurification by chromatography on a silica column, eluted with a mixtureof dichloromethane and heptane (60/40).

(b) Synthesis of syn-4-α-benzyloxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoicacid:

Following the basic procedure of Example 2, beginning with 2.6 g (5mmol) of allyl syn-4-α-benzyloxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoate,1.7 g (71% ) of the expected acid of melting point 223°-5° C. wasobtained.

EXAMPLE 17 Preparation of syn-4-α-methoxyethoxymethoxyimino-(5,6,7.8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoicacid

(a) Preparation of allyl syn-4-α-methoxyethoxymethoxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!-benzoate:

Following the basic procedure of Example 1 (f), 3.3 g (7.6 mmol) ofallyl 4-α-hydroxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2napthyl)acetamido!benzoatewere reacted with 870 μl (7.6 mmol) of methoxyethoxymethane chloride.1.2 g (30%) of the expected allyl ester was recovered in the form of achestnut-colored oil after purification by chromatography on a silicacolumn, eluted with a mixture of dichloromethane and heptane (70/30).

(b) Synthesis of syn-4-α-methoxyethoxymethoxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!-benzoicacid:

Following the basic procedure of Example 2, beginning with 1.1 g (2.1mmol) of allyl syn-4-α-methoxyethoxy-methoxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoate,780 mg (77%) of the expected acid of melting point 113°-15° C. wereobtained.

EXAMPLE 18 Preparation of allyl syn-4-α-ethoxycarbonylpropylimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoate

Following the basic procedure of Example 1 (f), 3.9 g (9 mmol) of allyl4-α-hydroxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoatewere reacted with 2.8 g (9 mmol) of ethyl 8-bromooctanoate. 2.4 g (50%)of the expected allyl ester were recovered in the form of a colorlessoil after purification by chromatography on a silica column, eluted withdichloromethane.

EXAMPLE 19 Preparation of (Z)-4-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-nonenamido!benzoicacid

(a) Preparation of2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-nonenoic acid:

1 g (3.8 mmol) of5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylglyoxylic acid and 10ml of DMSO were introduced into a three-necked flask under a nitrogenstream. 2.37 ml of n-BuLi (1.6 M in hexane) were added dropwise and themixture was stirred at room temperature for 15 minutes. 2 g (4.5 mmol)of n-heptyltriphenylphosphine bromide were then added and 2.85 ml (4.5mmol) of n-BuLi (1.6 M in hexane) were added dropwise and the mixturewas stirred at room temperature for one hour. The reaction medium waspoured into water, adjusted to pH 1 with hydrochloric acid, extractedwith ethyl ether, the organic phase decanted off, dried over magnesiumsulfate and evaporated. The residue obtained was purified bychromatography on a silica column, eluted with a mixture of ethyl etherand heptane (40/60). 380 mg (28%) of the expected compound wererecovered in the form of an oil after evaporation of the solvents.

(b) Preparation of2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-nonenoylchloride:

1.7 g (5 mmol) of2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-nonenoic acid,20 ml of toluene and 73 μl of DMF were introduced into a round-bottomedflask. The mixture was heated to 50° C. and 714 μl (6 mmol) of thionylchloride were added and the mixture was stirred at this temperature forone hour. The mixture was evaporated to dryness and the crude acidchloride was employed as is in the synthesis to follow.

(c) Preparation of methyl (Z)- and (E)-4-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-nonenamido!benzoate:

830 mg (5.5 mmol) of methyl 4-aminobenzoate, 20 ml of THF and 612 μl (6mmol) of triethylamine were introduced into a three-necked flask under anitrogen stream. The acid chloride prepared above, dissolved in 10 ml ofTHF, was added dropwise and the mixture was stirred at room temperaturefor eight hours. The reaction medium was poured into water, extractedwith ethyl ether, the organic phase decanted off, dried over magnesiumsulfate and evaporated. A mixture of the two geometric isomers wasrecovered, which isomers were separated by chromatography on a silicacolumn, eluted with a mixture of dichloromethane and heptane (65/35).The following compounds were recovered:

(i) 1 g (42%) of methyl (Z)-4-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-nonenamido!benzoateof melting point 129°-30° C.

(ii) 400 mg (18%) of methyl (E)-4-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-nonenamido!benzoateof melting point 86°-7° C.

(d) Synthesis of (Z)-4-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-napthyl)-2-nonenamido!benzoicacid:

700 mg (1.47 mmol) of methyl (Z)-4-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-nonenamido!benzoate,25 ml of methanol and 1.2 ml (14.7 mmol) of a 35% sodium hydroxidesolution were introduced into a round-bottomed flask. The mixture wasstirred at room temperature for 12 hours, the reaction medium was pouredinto water, acidified to pH 1 with hydrochloric acid (37%), extractedwith ethyl ether, the organic phase decanted off, dried over magnesiumsulfate and evaporated. The residue was triturated in heptane, filteredand dried. 555 mg (82%) of (Z)-4-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-nonenamido!benzoicacid of melting point 183°-4° C. were recovered.

EXAMPLE 20 Preparation of (E)-4-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-hexadecenamido!benzoicacid

(a) Preparation of2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-hexadecenoicacid:

Following the basic procedure of Example 19 (a), 9.65 g (37.1 mmol) of5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylglyoxlic acid werereacted with 24 g (44.5 mmol) of tetradecyltriphenylphosphine bromide.4.53 g (28%) of the expected compound of melting point 59°-60° C. wereobtained in the form of an oil which crystallized slowly afterpurification on a silica column, eluted with dichloromethane.

(b) Preparation of2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-hexadecenonylchloride:

Following the basic procedure of Example 19 (b), 2 g (4.5 mmol) of2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-hexadecenoicacid were reacted with 648 μl (5.4 mmol) of thionyl chloride. The acidchloride obtained was employed as is, in the crude form, in thesynthesis to follow.

(c) Preparation of methyl (Z)-4-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-hexadecenamido!benzoate:

Following the basic procedure of Example 19 (c), the acid chlorideobtained above was reacted with 755 mg (5 mmol) of methyl4-aminobenzoate. 1.16 g (42%) of methyl (Z)-4-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-hexadecenamido!benzoateof melting point 93°-4° C. was obtained after chromatography on a silicacolumn, eluted with a mixture of dichloromethane and heptane (50/50).(d) Synthesis of (Z)-4-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-hexadecenamido!benzoicacid

Following the basic procedure of Example 19 (d), beginning with 503 mg(0.9 mmol) of methyl (Z)-4-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-hexadecenamido!benzoate,435 mg (89%) of (Z)-4-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-hexadecenamido!benzoicacid of melting point 164°-5° C. were obtained.

EXAMPLE 21

In this example, various specific formulations based on the compoundsaccording to the invention are illustrated.

    ______________________________________    (A) ORAL ROUTE:    ______________________________________    (a) 0.2 g Tablet:    (i) Compound prepared in Example 3                             0.001 g    (ii) Starch              0.114 g    (iii) Dicalcium phosphate                             0.020 g    (iv) Silica              0.020 g    (v) Lactose              0.030 g    (vi) Talc                0.010 g    (vii) Magnesium stearate 0.005 g    (b) Oral suspension in 5 ml ampoules:    (i) Compound prepared in Example 4                             0.001 g    (ii) Glycerine           0.500 g    (iii) Sorbitol at 70%    0.500 g    (iv) Sodium saccharinate 0.010 g    (v) Methyl parahydroxybenzoate                             0.040 g    (vi) Flavoring       qs    (vii) Purified water    qs                             5 ml    ______________________________________    (B) TOPICAL ROUTE:    ______________________________________    (a) Ointment:    (i) Compound of Example 3                             0.020 g    (ii) Isopropyl myristate 81.700 g    (iii) Fluid paraffin oil 9.100 g    (iv) Silica ("Aerosil 200" marketed                             9.180 g      by DEGUSSA)    (b) Ointment:    (i) Compound of Example 5                             0.300 g    (ii) Petroleum jelly     100 g    (c) Non-ionic water-in-oil cream:    (i) Compound of Example 4                             0.100 g    (ii) Mixture of emulsive lanolin                             39.900 g      alcohols, waxes and oils      ("anhydrous Eucerin" marketed by      BDF)    (iii) Methyl parahydroxybenzoate                             0.075 g    (iv) Propyl parahydroxybenzoate                             0.075 g    (v) Sterile demineralized water qs                             100 g    (d) Lotion:    (i) Compound of Example 5                             0.100 g    (ii) Polyethylene glycol (PEG 400)                             69.900 g    (iii) Ethanol at 95%     30.000 g    (e) Hydrophobic ointment:    (i) Compound of Example 2                             0.300 g    (ii) Isopropyl myristate 36.400 g    (iii) Silicone oil ("Rhodorsil 47 V                             36.400 g      300" marketed by RHONE-POULENC)    (iv) Beeswax             13,600 g    (v) Silicone oil ("Abil 300.000 cst"                             100 g      marketed by GOLDSCHMIDT)    (f) Non-ionic oil-in-water cream:    (i) Compound of Example 3                             1.000 g    (ii) Cetyl alcohol       4.000 g    (iii) Glycerol monostearate                             2.500 g    (iv) PEG 50 stearate     2.500 g    (v) Shea butter          9.200 g    (vi) Propylene glycol    2.000 g    (vii) Methyl parahydroxybenzoate                             0.075 g    (viii) Propyl parahydroxybenzoate                             0.075 g    (ix) Sterile demineralized water                             100 g    ______________________________________

While the invention has been described in terms of various preferredembodiments, the skilled artisan will appreciate that variousmodifications, substitutions, omissions, and changes may be made withoutdeparting from the spirit thereof. Accordingly, it is intended that thescope of the present invention be limited solely by the scope of thefollowing claims, including equivalents thereof.

What is claimed is:
 1. A biaromatic amido compound having the structuralformula (I): ##STR7## in which Ar is a radical (a): ##STR8## in which Zis --CO--NR₇ --; R₁ is (i) a --CH₃ radical, (ii) a radical --CH₂--O--R₆, (iii) a radical --O--R₆, (iv) a radical --CO--R₈ or (v) aradical --S(O)_(t),R₉ ; X and Y together form, with the carbon atom fromwhich they depend, a single radical containing a double bond, selectedfrom the group consisting of the formulae ═N--O--(CH₂)_(n) --R₁₀,═CH--(CH₂)_(m) --R₁₀, ═N--O--(CH₂)₂ --O--CH₂ --CH₃, ═N--O--CH₂ --O--CH₂--CH₂ --O--CH₃ and ═CH--(CH₂)_(m) --CH₃ ; R₂ and R₃, taken separately,are each a hydrogen atom, a linear or branched alkyl radical having from1 to 20 carbon atoms, a radical --OR₆ or a radical --SR₆, with theproviso that R₂ and R₃ cannot simultaneously be a hydrogen atom, aradical --OR₆ or a radical --SR₆, or R₂ and R₃ together form, with theadjacent aromatic ring from which they depend, a 5- or 6-membered ringwhich is optionally substituted by methyl radicals or is optionallyinterrupted by an oxygen or sulfur atom or by an --SO-- or --SO₂ --radical on which is both optionally substituted by methyl radicals andfurther optionally interrupted by an oxygen or sulfur atom or by an--SO-- or --SO₂ -- radical; R₄ is a hydrogen atom, a halogen atom, alower alkyl radical or a radical --OR₆, wherein R₅ has the samedefinition as R₄ ; R₆ is a hydrogen atom, a linear or branched alkylradical having from 1 to 20 carbon atoms or a radical --CO--R₁₁ ; R₇ isa hydrogen atom or a lower alkyl radical; R₈ is (a) a hydrogen atom, (b)a lower alkyl radical, (c) a radical of the formula: ##STR9## or (d) aradical --OR₁₂, R₉ and R₁₁, which may be identical or different, areeach a lower alkyl radical; R₁₀ is (i) a radical --OR₆, (ii) a radical--CO--R₈, (iii) a radical of the formula: ##STR10## (iv) an optionallysubstituted aryl radical, (v) a heterocyclic radical selected from thegroup consisting of piperidino, morpholino, pyrrolidino and piperazino,which can optionally be substituted at the 4-position by a C₁ -C₆ alkylradical or a mono- or polyhydroxyalkyl radical, or (vi) a C₃ or C₆cycloaliphatic radical; R₁₂ is a hydrogen atom, a linear or branchedalkyl radical having from 1 to 20 carbon atoms, an alkenyl radical, amono- or polyhydroxyalkyl radical, an optionally substituted aryl oraralkyl radical; R' and R", which may be identical or different, areeach a hydrogen atom, a lower alkyl radical, a mono- or polyhydroxyalkylradical, an optionally substituted aryl radical wherein R' and R" maytogether form, with the nitrogen atom from which they depend, aheterocycle selected from the group consisting of piperidino,morpholino, pyrrolidino and piperazino, which can optionally besubstituted at the 4-position by a C₁ -C₆ alkyl radical or a mono- orpolyhydroxy radical; m is an integer ranging from 1 to 20; n is aninteger ranging from 2 to 20; and t is an integer equal to 0, 1 or 2; ora pharmaceutically/cosmetically salt or geometric or optical isomerthereof.
 2. A biaromatic amido compound as defined by claim 1, where informula (I), Ar has the structure (a).
 3. A biaromatic amido compound asdefined by claim 1, comprising a pharmaceutically acceptable saltthereof.
 4. A biaromatic amido compound as defined by claim 1, where informula (I), the lower alkyl radical substituents are selected from thegroup consisting of methyl , ethyl, isopropyl, butyl, tert-butyl andhexyl radicals.
 5. A biaromafic amido compound as defined by claim 1,where in formula (I), the lower alkyl radical substituents are selectedfrom the group consisting of methyl, ethyl, propyl, 2-ethylhexyl, octyl,dodecyl, hexadecyl and octadecyl radicals.
 6. A biaromatic amidocompound as defined by claim 1, where in formula (I), themonohydroxyalkyl radical substituents are selected from the groupconsisting of 2-hydroxypropyl and 3-hydroxypropyl radicals.
 7. Abiaromatic amido compound as defined by claim 1, where in formula (I),the polyhydroxyalkyl radical substituents are selected from the groupconsisting of 2,3-diydroxypropyl, 2,3,4-trihydroxybutyl,2,3,4,5-tetrahydroxypentyl and pentaerythritol radicals.
 8. A biaromaticamido compound as defined by claim 1, where in formula (I), the arylradical is a phenyl radical which is optionally substituted by at leastone halogen atom, or at least one hydroxyl or nitro functional group. 9.A biaromatic ado compound as defined by claim 1, where in formula (I),the aralkyl radical is selected from the group consisting of benzyl andphenethyl radicals which may be optionally substituted by at least onehalogen atom, or at least one hydroxyl or nitro functional group.
 10. Abiaromatic amido compound as defined by claim 1, where in formula (I),the alkenyl radical substituents have from 1 to 5 carbon atoms andcomprise at least one site of ethylenic unsaturation.
 11. A biaromaticamido compound as defined by claim 1, where in formula (I), theheterocyclic radical substituents are selected from the group consistingof piperidino, morpholino, pyrrolidino and piperazino radicals which areoptionally substituted by a C₁ -C₆ alkyl radical or a mono- orpolyhydroxyalkyl radical.
 12. A biaromatic amido compound as defined byclaim 1, where in formula (I), the halogen atom substituents areselected from the group consisting of fluorine, chlorine and bromineatoms.
 13. A biaromatic amido compound as defined by claim 1, selectedfrom the group consisting of anti-4-α-hydroxyhexylimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoicacid; syn-4α-hydroxyhexylimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoicacid; syn-4α-methoxycarbonylpentylimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoicacid; syn-4-α-hydroxyoctyloxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoicacid; trans-4-α-hydroxyoctyloxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoicacid; syn-4-α-hydroxyheptyloxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoicacid; trans-4-α-hydroxyheptyloxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoicacid; syn-4-α-hydroxypropyloxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoicacid; trans-4-α-hydroxypropyloxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoicacid; syn-4-α-ethoxycarbonylpropyloxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoicacid; syn-4-α-hydroxydecyloxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!-benzoicacid; syn-4-α-hydroxynonyloxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!-benzoicacid; syn-4-α-benzyloxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!-benzoicacid; syn-4-α-methoxyethoxymethoxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoicacid; allyl syn-4-α-ethoxycarbonylpropyloxyimino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido!benzoate;(E)-4-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-nonenamido!benzoicacid; (Z)-4-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-nonenamido!benzoicacid; (E)-4-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-undecenamido!benzoicacid; (E)-4-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-undecenamido!phenyl-carboxamide;(E)-4-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-undecenamido!benzenemethanol;(E)-4-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-undecenamido!phenol;(Z)-4-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-undecenamido!benzoicacid; (E)-4-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-hexadecenamido!benzoicacid; and (Z)-4-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl2-naphthyl)-2-hexadecenamido!benzoicacid.
 14. A biaromatic amido compound as defined by claim 1, where informula (I), R₁ is the radical --COR₈ and X and Y together form aradical selected from the group consisting of the formulae═N--O--(CH₂)_(n) --R₁₀, ═CH--(CH₂)_(m) --R₁₀, ═N--O--(CH₂)₂ --O--CH₂--CH₃, ═N--O--CH₂ --O--CH₂ --CH₂ --O--CH₃ or ═CH--(CH₂)_(m) --CH₃.
 15. Apharmaceutical composition of matter, comprising a therapeuticallyeffective amount of a biaromatic amido compound as defined by claim 1,or pharmaceutically acceptable salt or isomer thereof, and apharmaceutically acceptable carrier, diluent or vehicle therefor. 16.The pharmaceutical composition as defined by claim 15, furthercomprising a retinoid compound, a D vitamin, a corticosteroid, ananti-free radical agent, an α-hydroxy or α-keto acid, an ion channel,blocker, or combination thereof.
 17. The pharmaceutical composition asdefined by claim 15, comprising a tablet, a capsule, a syrup, asuspension, an elixir, a solution, a powder, granules, an emulsion,microspheres, nanospheres, lipid vesicles, polymeric vesicles, or aninjectable.
 18. The pharmaceutical composition as defined by claim 15,comprising an ointment, a cream, a milk, a pommade, an impregnated pad,a gel, a spray, or a lotion.
 19. The pharmaceutical composition asdefined by claim 15, adopted for topical administration.
 20. Thepharmaceutical composition as defined by claim 15, adopted for systemicadministration.
 21. The pharmaceutical composition as defined by claim15, comprising from 0.001% to 5% by weight of said biaromatic amidocompound, or salt or isomer thereof.
 22. The pharmaceutical compositionas defined by claim 15, further comprising a wetting agent, adepigmenting agent, a moisturizing agent, an antiseborrhoeic or antiacneagent, an antibiotic, an antifungal agent, a hair regrowth promoter, anon-steroidal anti-inflammatory agent, a carotenoid, an anti-psoriaticagent, 5,8,11,14-eicosatetraynoic or 5,8,11-eicosatrynoic acid or esteror amide thereof, or combination thereof.
 23. The pharmaceuticalcomposition as defined by claim 15, further comprising a taste- orflavor-enhancing agent, a preservative, a stabilizer, a moistureregulating agent, a pH regulating agent, an osmotic pressure modifyingagent, an emulsifying agent, a UV-A or UV-B screening agent, anantioxidant, or combination thereof.
 24. A cosmetic composition ofmatter, comprising a cosmetically effective amount of a biaromatic amidocompound as defined by claim 1, or cosmetically acceptable salt orisomer thereof, and a cosmetically acceptable carrier, diluent orvehicle therefor.
 25. The cosmetic composition as defined by claim 24,comprising a cream, a milk, a lotion, a gel, microspheres, nanospheres,lipid vesicles, polymeric vesicles, a soap, or a shampoo.
 26. Thecosmetic composition as defined by claim 24, comprising from 0.001% to3% by weight of said biaromatic amido compound, or salt or isomerthereof.
 27. The cosmetic composition as defined by claim 24, furthercomprising a retinoid compound, a D vitamin, a corticosteroid, ananti-free radical agent, an α-hydroxy or α-keto acid, an ion channelblocker, or combination thereof.
 28. The cosmetic composition by claim22, further comprising a wetting agent, a depigmenting agent, amoisturizing agent, an antiseborrhoeic or antiacne agent, an antibiotic,an antifungal agent, a hair regrowth promoter, a non-steroidalanti-inflammatory agent, a carotenoid, an anti-psoriatic agent,5,8,11,14-eicosatetraynoic or 5,8,11-eicosatrynoic acid or ester oramide thereof, or combination thereof.
 29. The cosmetic composition asdefined by claim 22, further comprising a taste- or flavor-enhancingagent, a preservative, a stabilizer, a moisture regulating agent, a pHregulating agent, an osmotic pressure modifying agent, an emulsifyingagent, a UV-A or UV-B screening agent, an antioxidant, or combinationthereof.